Biology subjects

Rizzo, N.

Publications and source records attributed to Rizzo, N..

4 recordsLinked to original sources

bioRxiv2026

Genomic analysis of BCG unresponsive non-muscle-invasive bladder cancer identifies drivers of sensitivity to intravesical Gemcitabine/Docetaxel

Background and ObjectivesIntravesical gemcitabine/docetaxel (Gem/Doce) is an effective therapy for Bacillus Calmette- Guerin (BCG)-unresponsive non-muscle-invasive bladder cancer (NMIBC), achieving 50% complete responses at 2 years. However, the genomic determinants underlying response and resistance to Gem/Doce remain poorly defined. Our objective was to define the mutational landscape of BCG-unresponsive NMIBC and nominate genomic features associated with response or resistance Gem/Doce. MethodsPatients with BCG-unresponsive NMIBC treated with Gem/Doce were classified as responders (recurrence-free survival [RFS] >12 months) or non-responders (RFS <12 months). Whole-exome sequencing was performed on tumors prior to Gem/Doce treatment (n=23). Single nucleotide variants were identified and annotated using a Cancer Genome Analysis pipeline. Copy number alterations were inferred with ABSOLUTE, and clonal architecture was reconstructed using PhylogicNDT. Key Findings and LimitationsResponders demonstrated significantly prolonged time to high-grade recurrence (3.5 vs 42 months, p<0.001) and cystectomy compared with non-responders (9.5 months vs not reached; p<0.001). Non-responders exhibited higher tumor mutational burden (13.66 vs 8.71; p=0.02) and more frequent whole-genome doubling (2/2 non-responders vs 0/1 responders; p=0.33). Phylogenetic analyses revealed clonal BAP1 and subclonal BRCA2 mutations in responders, whereas non-responders harbored clonal FGFR3 mutations. Limitations include small sample size and retrospective design. Conclusions and Clinical ImplicationsDistinct genomic features underlie differential response to Gem/Doce in BCG-unresponsive NMIBC. In responders, alterations in DNA repair pathways (e.g., BRCA2) may sensitize tumors to chemotherapy, while non-responders with FGFR3 mutations may benefit from alternative targeted strategies. These findings warrant validation in larger cohorts and support the development of biomarker-driven clinical trials. Patient summaryIn this report we analyzed bladder tumors and found that some tumors respond well to treatment because they have defects in repairing DNA, making them more vulnerable to chemotherapy. In contrast, tumors that do not respond to chemotherapy harbor different genetic changes that help them survive and grow. These findings may help physicians choose more effective and personalized treatments in the future.

genomics↗

bioRxiv2025

Effects of Tilia tomentosa on sleep architecture and circadian rhythm

Tilia extract has been used for centuries as a sedative and hypnotic compound. The impact of Tilia on sleep architecture and circadian rhythm remained, however, elusive. Here, we addressed these open questions by analysing the behaviour and the EEG signals recorded in freely moving mice fed an enriched diet with Tilia extracts. We found that Tilia significantly increased the amount of sleep, mostly during the dark hours, which correspond to the most active phase in nocturnal animals, such as mice. Furthermore, in darkness, the length of wake episodes did not increase as in controls. Spectral analyses of the EEG showed that the features of the sleep and wake signals remained unaltered upon Tilia treatment. Interestingly, the power in the gamma band resulted significantly decrease while the theta band power resulted increased in treated mice. Altogether, our data demonstrated a clear effect of Tilia on sleep architecture, highlighting its dependency on the circadian rhythm.

neuroscience↗

bioRxiv2024

Exploiting uniqueness: seed-chain-extend alignment on elastic founder graphs

Sequence-to-graph alignment is a central challenge of computational pangenomics. To overcome the theoretical hardness of the problem, state-of-the-art tools use seed-and-extend or seed-chain-extend heuristics to alignment, therefore reducing the computational resources required for the task. However, two main problems still remain: on the one hand, the daunting amount of sequencing data requires us to trade alignment accuracy with computational resources; on the other hand, current graph representations of pangenomes introduce an excessive amount of spurious recombinations. In this paper, we implement a complete seed-chain-extend alignment workflow based on indexable elastic founder graphs (iEFGs), a class of graphs built from aligned sequences and supporting fast pattern matching while reducing the number of artificial recombinations. We show how to construct iEFGs from the variations to a linear reference, find high-quality seeds, and extend them using GraphAligner, at the scale of a telomere-to-telomere assembled human chromosome. The main ingredient of our workflow is the use and the efficient computation of semi-repeat-free seeds (srf), a novel class of iEFG-based seeds introduced in this work. The amount of srf seeds is two orders of magnitude less than that of minimizers at the human chromosome level while maintaining comparable speed. Thanks to the uniqueness properties of iEFGs, we show that srf-based seeds suffice to maintain high accuracy while leveraging the speed of our tool. To further stress our point, we also implement chaining of seeds on the elastic degenerate string relaxation of the iEFG and show that only chained seeds suffice to achieve high accuracy alignments. Our sequence-to-graph alignment tool and the scripts to replicate our experiments are available in https://github.com/algbio/SRFAligner.

bioinformatics↗

bioRxiv2024

Microbiome Modulation Uncouples Efficacy and Toxicity Induced by Programmed Death-1/Programmed Death-Ligand1 Blockade

While asymptomatic smoldering multiple myeloma (SMM) holds an overall risk of progression to multiple myeloma (MM) at 10% per year, only active surveillance is offered to most patients affected by SMM, which leaves them in anxiety and frustration. Intestinal microbiota and gut-born T helper 17 (Th17) lymphocytes may act as drivers of MM evolution. In transgenic Vk*MYC mice developing de novo MM, which invariably evolves from Early-MM that mimics SMM to full-blown Late-MM, we investigated the impact of gut microbiota modulation on disease progression and susceptibility to immune checkpoint blockade (ICB). We report that administering the human commensal Prevotella melaninogenica to mice affected by Early-MM significantly delayed evolution to Late-MM. Mechanistically, treatment with P. melaninogenica induced increased production of short chain fatty acids. Butyrate prevented skew of dendritic cells towards a pro-Th17 phenotype and treated mice accumulated less disease induced Th17 cells in their bone marrow. P. melaninogenica also synergized with anti-PD-L1 antibodies by restraining Th17 cell expansion while unleashing ICB-induced full effector CD8+ T cells, eventually blocking progression to full-blown disease. Similar results were obtained in mice challenged with bortezomib-resistant Vk*MYC tumor cells, a model of more aggressive MM. When mice were exposed to imiquimod to mimic ICB-associated psoriasis-like lesions, P. melaninogenica ameliorated skin lesions caused by ICB. Thus, modulation of the gut microbiota with P. melaninogenica might represent a treatment for patients affected by SMM and would allow fully exploiting the antitumor potential of ICB in plasma cell dyscrasias. Key pointsAdministration of the human commensal Prevotella melaninogenica to Vk*MYC mice delayed evolution to symptomatic multiple myeloma; P. melaninogenica therapeutically synergized with PD-1/PD-L1 blockade also limiting immune-related adverse events.

immunology↗